The biological activities of erythropoietin, the cytokine required for red blood cell production, have been found to extend to non-erythroid tissues due to the expression of the erythropoietin receptor. Erythropoietin promotes metabolic activity and increases mitochondrial function in white adipocytes. Mice with erythropoietin receptor restricted to erythroid tissue exhibit an increase in fat mass but a decrease in fat cell size that indicates an increase in adipocyte number, suggesting that endogenous erythropoietin signaling negatively regulates adipocyte number. Conversely, erythropoietin treatment in wild type mice on regular chow diet or high fat diet increases fat cell size although fat mass accumulation and weight gain decreases. Hyperplasia is more prominent than hypertrophy in high fat diet induced obesity and the weight loss effect of erythropoietin is more apparent in obese mice. In preadipocyte cultures, erythropoietin reduces PPARgamma activation and reduces cell number and adipocyte differentiation. These data suggest a role for erythropoietin in adipocyte remodeling in which erythropoietin suppresses adipocyte differentiation and adipocyte number while increasing adipocyte lipid accumulation, and thereby contributes to the decrease in total fat mass and weight gain in mice.